International Journal of Clinical Pharmacology and Therapeutics Vol. 33, No 4, 1995

E. Wong, G. Lee, J. Cucherman, and D.T. Mason

Female office workers with desk jobs who are incapacitated by pain and tingling in the hands and fingers are often diagnosed by physicians as "repetitive stress injury" (RSI) or "carpal tunnel syndrome" (CTS). These patients usually have poor posture with their head and neck stooped forward and shoulders rounded; upon palpation, they have pain and tenderness at the spinous processes C5-T1 and the medial angle of the scapula. In 35 such patients we focused the treatment primarily at the posterior neck area and not the wrists and hands. A low level laser (100 mW) was used and directed at the tips of the spinous processes C5-T1. The laser rapidly alleviated the pain and tingling in the arms, hands and fingers, and diminished tenderness at the involved spinous processes. Thereby, it has become apparent that many patients labelled as having RSI or CTS have predominantly cervical radicular dysfunction resulting in pain to the upper extremities which can be managed by low level laser. Successful long-term management involves treating the soft tissue lesions in the neck combined with correcting the abnormal head, neck and shoulder posture by taping, cervical collars, and clavicle harnesses as well as improved work ergonomics.

Cerebral hypometabolism characterizes mild cognitive impairment and Alzheimer's disease. Low-level light therapy (LLLT) enhances the metabolic capacity of neurons in culture through photostimulation of cytochrome oxidase, the mitochondrial enzyme that catalyzes oxygen consumption in cellular respiration. Growing evidence supports that neuronal metabolic enhancement by LLLT positively impacts neuronal function in vitro and in vivo. Based on its effects on energy metabolism, it is proposed that LLLT will also affect the cerebral cortex in vivo and modulate higher-order cognitive functions such as memory. In vivo effects of LLLT on brain and behavior are poorly characterized. We tested the hypothesis that in vivo LLLT facilitates cortical oxygenation and metabolic energy capacity and thereby improves memory retention. Specifically, we tested this hypothesis in rats using fear extinction memory, a form of memory modulated by prefrontal cortex activation. Effects of LLLT on brain metabolism were determined through measurement of prefrontal cortex oxygen concentration with fluorescent quenching oximetry and by quantitative cytochrome oxidase histochemistry. Experiment 1 verified that LLLT increased the rate of oxygen consumption in the prefrontal cortex in vivo. Experiment 2 showed that LLLT-treated rats had an enhanced extinction memory as compared to controls. Experiment 3 showed that LLLT reduced fear renewal and prevented the reemergence of extinguished conditioned fear responses. Experiment 4 showed that LLLT induced hormetic dose-response effects on the metabolic capacity of the prefrontal cortex. These data suggest that LLLT can enhance cortical metabolic capacity and retention of extinction memories, and implicate LLLT as a novel intervention to improve memory.

INTRODUCTION

Low-level light therapy (LLLT) with red to near-infrared light is a promising and novel neurotherapeutic intervention in animals and humans. Lasers use low-energy irradiation that avoids ablative effects on tissues, yet such energy is high enough to modulate cell functions. LLLT has well-established beneficial effects in nervous system tissue in vitro and in vivo, including enhancement of gene expression and nerve regeneration, and protection against traumatic injury, ischemic damage, and neurodegeneration induced by mitochondrial dysfunction. The mechanism of action of LLLT implicates light absorption by chromophores in the mitochondrial respiratory enzyme cytochrome oxidase (also called cytochrome c oxidase). LLLT facilitates cell respiration and energy production in metabolically active tissues. Tissues with high oxidative metabolic rates such as brain and muscle show increases of cytochrome oxidate after in vivo LLLT. Enhancement of cell respiration and cytochrome oxidase upregulation are believed to underlie a series of secondary effects that promote neuroprotection. A largely unexplored area of photobiology comprises the effects of LLLT on higher-order cognitive functions. Recent reports suggest the LLLT can be used non-invasively to exert transcranial brain metabolic effects in rodents and humans. However, LLLT exhibits a hormetic dose-response effect characterized by stimulation of a biological process at a low dose and inhibition of that process at a high dose. Thus LLLT may be anticipated to facilitate memory at low doses but show opposite effects at high doses. Hypothesized that by enhancing mitochondrial respiration and energy metabolic capacity in specific neural networks, low dose LLLT may also have beneficial impact on processes such as learning and memory.

DISCUSSION

This study is the first demonstration that LLLT can improve extinction memory. This study also presents evidence that both primary and secondary LLLT effects occur in the brain in vivo. The results add to the growing body of in vitro and in vivo evidence supporting that LLLT can be used non-invasively to modulate neural function. Red and near-infrared light transmittance has been measured through the mouse skull and its transcranial neuroprotective effects have been demonstrated in the mouse, rat, and rabbit. Human experiments have also demonstrated changes in frontal cortex regional cerebral blood flow after exposure to LLLT in the forehead. Several reports have described beneficial effects of LLLT on cognition. Reported improvement of attention, executive function, and memory in two patients with chronic traumatic brain injury with daily use of LLLT to the head. Reports in rats and humans provide further evidence that LLLT modulates mood and decreases depressive symptoms. Taken together, the data supports that LLLT to the head constitutes a promising neurotherapeutic tool to modulate behavior in a non-invasive manner.

This study is also the first demonstration that both primary and secondary mechanisms of action of LLLT occur in the brain in vivo. Primary LLLT effects occur during light exposure and refer to the direct photochemical change of the photoacceptor (e.g., cytochrome oxidase) upon excitation by light. The most important primary effect is a redox change of the components of the respiratory chain that affects electron flow. Support that primary effects of LLLT occur in the brain in vivo is provided by the dose-response increase in oxygen consumption measured in the frontal cortex of rats exposed to LLLT in this study.

Treatment with acetyl-L-carnitine and similar compounds may be augmented by LLLT, which can further increase mitochondrial energy production and cerebral flow. LLLT increases cytochrome oxidase and superoxide dismutase activities, without inducing any apparent adverse effects at radiant exposure doses described in this and previous studies. Since memory functions are extremely sensitive to oxidative energy deficits, it is likely that cytochrome oxidase inhibition linked to impairments in cerebral vascular perfusion may underlie memory deficits and eventually contribute to brain cell atrophy and degeneration. Therefore, LLLT should be tested in people with cognitive and memory impairment as a safe and potentially effective alternative or complement to existing pharmacological interventions.

It is expected that the beneficial effects of LLLT will have applications in other forms of learning and memory besides extinction. It is possible the LLLT potentially reaches all brain regions but will selectively enhance those with higher energy demands due to task-dependent activation. It is expected to occur in states of increased energy consumption, such as those of neuronal networks activated during a particular task. In other words, greater photoneurostimulation is expected in highly metabolically active regions.

Lower LLLT doses, but not higher doses, included a significant increase in brain cytochrome oxidase 24h after treatment. It is believed that far from being a spurious result, this hormetic responce on neurometabolic stimulation is representative of distinctive and well-characterized dose-responce effect of LLLT. Hormesis describes a dose-responce effect in which there is stimulation of a biological process at a low dose and no effect or even inhibition of that process at a high dose.

In the case of LLLT, extensive in vitro data suppport photostimulatory effects with lower doses and inhibition with higher doses. Our data can be interpreted as supportive of the current mechanistic paradigm of LLLT that implicates hormetic enhancement of energy metabolism.

In conclusion, this study demonstrated that LED-based LLLT is a non-invasive intervention without significant side effects that can enhance cortical metabolic capacity and facilitate retention of extinction memory. These results implicate LLLT as a potential intervention to improve memory in humans.

This study was supported in part by the National Institutes of Health.

It was not long after the discovery of the first lasers (the ruby laser in 1960 and the helium-neon [HeNe] laser in 1961) that they began to be used in medical applications. In 1967, Endre Mester in Hungary noticed the ability of the HeNe laser to increase hair growth and stimulate wound healing in mice, and, shortly afterward, he began to use lasers to treat patients with nonhealing skin ulcers. Since those early days, the use of low-power lasers (as opposed to high-power lasers that can destroy tissue by a photothermal effect) has steadily increased in diverse areas of medical practice that require healing, prevention of tissue death, pain relief, reduction of inflammation, and regenerative medicine. Some of the different organ systems, diseases, and injuries that have been effectively treated with low-level laser therapy (LLLT) are schematically shown below.

SPINAL CORD INJURY

SCI is a severe central nervous system trauma with no effective restorative therapies. Light therapy has biomodulatory effects on central and peripheral nervous tissue. Several groups investigated the effectiveness of LLLT on SCI. Roch-kind et al demonstrated that LLLT applied simultaneously to the injured sciatic nerve and the corresponding segment of the spinal cord accelerates the process of regeneration of the injured peripheral nerve.

TRAUMATIC BRAIN INJURY

The researchers suggested various possible mechanisms, including an increase in ATP, total antioxidants, angiogenesis, neurogenesis, heat shock proteins content, and an antiapoptotic effect, similar to observations reported after LLLT treatment of ischemic heart skeletal muscles. Both patients with TBI reported that they needed to continue with home treatments. If they stop treatment for 1 or 2 weeks, then their cognitive problems started to return. Both patients with TBI reported improved sleep. The second patient with TBI reported a decrease in her posttraumatic stress disorder symptoms after a few months of using the transcranial LEDs, and Schiffer et al also reported a reduction in posttraumatic stress disorder symptoms in 3 of 10 patients with major depression who were treated with transcranial LED.Several possible mechanisms may be associated with the improved cognition in the mTBI cases treated with transcranial LEDs. Mitochondria display a significant amount of dysfunction after TBI. The primary mechanism for improvement posited in one study with human acute stroke patients was an increase in ATP, with photons being used by CCO in the mitochondria to increase ATP, especially in the cortex.An increase in ATP after red and/or NIR LED treatments in patients with chronic TBI would have beneficial effects, including an increase in cellular respiration and oxygenation.

DEGENERATIVE CENTRAL NERVOUS SYSTEM DISEASE

The positive effects of transcranial laser therapy on stroke and TBI have led to early investigations into whether LLLT may have benefits for persons with degenerative brain disorders, which are a rapidly growing affliction of the world's aging population. Moges et al tested whether LLLT had a role to play in treating familial amyotrophic lateral sclerosis (FALS), which is a neurodegenerative disease characterized by progressive loss of motor neurons and death. Mitochondrial dysfunction and oxidative stress play an important role in motor neuron loss in ALS. The study combined LLLT (with use of an 810-nm diode laser with 140-mW output power targeting a 1.4-cm2 spot area for 120 seconds using 12 J/cm2 energy density) and riboflavin to test the survival of motor neurons in a mouse model of FALS. Motor function (determined with use of the Rota rod test) was significantly improved in the LLLT group in the early stage of the disease. Immunohistochemical expression of the astrocyte marker glial fibrillary acidic protein was significantly reduced in the cervical and lumbar enlargements of the spinal cord as a result of LLLT.

Trimmer et al carried out preliminary studies that may have relevance to Parkinson disease (PD). Mitochondria supply the ATP needed to support axonal transport, which contributes to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised.

CONCLUSION

LLLT is steadily moving into mainstream medical practice. As the Western populations continue to age, the incidence of the degenerative diseases of old age will only continue to increase and produce an evermore severe financial and societal burden. Moreover, despite the best efforts of “big pharma,” distrust of pharmaceuticals is growing in general because of uncertain efficacy and troublesome adverse effects. LLLT has no reported adverse effects, and no reports of adverse events can be directly attributed to laser or light therapy. We believe that the high benefit:risk ratio of LLLT should be better appreciated by medical professionals in the rehabilitation and physical medicine specialties. The introduction of affordable LED devices powered by rechargeable batteries will lead to many home-use applications of LLLT. The concept of “wearable” light sources is not far off. Moreover, the particular benefits of LLLT to both the central and peripheral nervous systems suggest that much wider use of LLLT could or should be made in cases of both brain diseases and injuries.

Five decades after the first documented use of a laser for wound healing, research in light therapy has yet to elucidate the underlying biochemical pathways causing its effects. The implication of cytochrome c oxidase as the photoacceptor modulating light therapy is reviewed, as are the predominant hypotheses of the biochemical pathways involved in the stimulation of wound healing, cellular proliferation, production of transcription factors and other reported stimulatory effects.

This year (2010) marks the 50th anniversary of the discovery of the laser. The development of lasers for medical use, which became known as low-level laser therapy (LLLT) or photobiomodulation, followed in 1967. In recent years, LLLT has become an increasingly mainstream modality, especially in the areas of physical medicine and rehabilitation. At first used mainly for wound healing and pain relief, the medical applications of LLLT have broadened to include diseases such as stroke, myocardial infarction, and degenerative or traumatic brain disorders. Mitochondria are thought to be the principal photo-receptors and increased adenosine triosphate, reactive oxygen species, intracellular calcium, and release of nitric oxide are the initial events. LLLT is relevant to neurology, such as stroke, traumatic brain injury, degenerative brain disease, spinal cord injury, and peripheral nerve regenerate.